Calacanis's biggest success to date is Weblogs, Inc., which was sold to AOL in 2005.
Before forming Weblogs, Inc., Calacanis was founder and CEO of Rising Tide Studios, a media company that published print and online publications. During the dot-com boom, Calacanis was active in New York's Silicon Alley community, and in 1996 began producing the Silicon Alley Reporter. Originally a 16-page photocopied newsletter, it eventually expanded into a 300-page magazine, with a sister publication called the Digital Coast Reporter for the West Coast. Calacanis' socializing earned him a nickname as the "yearbook editor" of the Silicon Alley community.[14] The company also organized conferences in New York, Los Angeles, and San Francisco focused on the Internet, web, and New Media. With the end of the Dot-com bubble, Silicon Alley Reporter failed, and the company was sold out of bankruptcy to a private equity firm.[15]

On November 16, 2006, TechCrunch reported that Calacanis had resigned from his position as CEO of Weblogs, Inc. and general manager of Netscape.[16] Calacanis later confirmed this on his blog and the Gillmor Gang podcast.[17][18]

Calacanis joined Sequoia Capital as an EIA (entrepreneur in action) in December, 2006,[19][20]
a position which he held until May, 2007.[21]

He launched the web directory Mahalo ("thank you" in Hawaiian), which raised $20 million in venture capital from investors including Sequoia Capital, News Corp, CBS, Mark Cuban, and Elon Musk. The company hit a peak of 15 million unique visitors a month and achieved profitability in 2011, but suffered a sharp decline in traffic that year from the Google Panda search algorithm update and shut down in 2014.[22]

Calacanis founded ThisWeekIn.com,[23] which in 2012, shut down. But now is again live and people can listen to it as a weekly podcast.[24]

ThisWeekInStartups.com (also called TWiSt) is a show hosted by Calacanis.[25][26]

In 2009, Calacanis founded the Open Angel Forum, an event that connects early-stage startups with angel investors. The forum was the culmination of a series of public comments by Calacanis questioning the ethics of pay-to-pitch angel forums.[27] Calacanis believes startups shouldn't have to pay to pitch angel investors, calling out fees that can range from $1,000 to $8,000 for a single 10- or 15-minute presentation.[28][29]

Calacanis raised a $10 million fund for his own venture investment firm to invest in startups that emerged from the Launch conference.[30][31] Limited partners in the fund include David Sacks.[32]
Following the success of the Launch conference,[33] Calacanis declared his intent to get closer and more involved in the new ventures that emerged from that conference.[34] The level of investment was around $25,000 to $100,000 in five to 10 startups per year.[35][36]

Calacanis publicly announced in 2018 that he sold all of his Facebook stock, expressing sharp criticism of company CEO and co-founder Mark Zuckerberg on the Too Embarrassed to Ask podcast. He called Zuckerberg "completely immoral" in how he runs the business and said, "No founder should ever sell a company to him."[37]

Calacanis authored a book titled "Angel: How to Invest in Technology Startups—Timeless Advice from an Angel Investor Who Turned $100,000 into $100,000,000" on angel investing published by HarperCollins in 2017.[38]